Resistance (R) loci with nucleotide binding/leucine rich repeat (NB-LRR or NLR) domains have been identified as the major causal genes for hybrid necrosis, which presents an extreme example of the trade-off between plant growth and the activation of immune system. This is an exciting finding both for plant breeders and plant pathologists. However, how these NLR proteins or even the whole NLR family lead to hybrid necrosis, how they contribute to fitness under natural conditions, and how this is reflected in their extreme sequence variation remain largely unknown. In this proposal, I plan to exhaustively explore their function by systematically knocking out the NLR loci from genome of different Arabidopsis accessions using genome editing, and testing their fitness performance in the natural habitat. I will also reveal the cellular and biochemical mechanisms by which NLR proteins inappropriately interact with other cellular proteins to cause hybrid necrosis and compare the hybrid necrosis activity with pathogen induced immunity.